The use of appetite supressants such as diethylproprion and phenylpropanolamine operate by directly and/or indirectly stimulating noradrenergic receptors in the brain. However, long-term use of these drugs is met with increasing tolerance in most patients, requiring increased dosage and more frequent administration to achieve continued appetite suppression. Tolerance to these products occurs as the result of a depletion of norepinephrine from storage sites in the neuron with the use of indirect-acting agents.
Catecholamines are stored in subcellular granules and released by exocytosis in the adrenal medulla and sympathetic nerve endings. The biosynthesis of catecholamines proceeds from the amino acid phenylalanine which is sequentially hydroxylated to form tyrosine, then 3,4-dihydroxyphenylalanine (DOPA). DOPA is decarboxylated to form dopamine. Hydroxylation on the beta position of the side chain forms norepinephrine.
The initial step, the hydroxylation of tyrosine, was believed to be rate-limited and regulated so that synthesis was coupled to release. This regulation has been thought to be achieved by alterations in both the activity and the amount of tyrosine hydroxylase. Harrison's Principles of Internal Medicine, 10th edition, edited by Petersdorf, R. G. et al, page 410 (1983).
After release by exocytosis, much of the norepinephrine is recaptured by an active reuptake mechanism. Additionally, norepinephrine is metabolized by O-methylation of the meta-hydroxyl group and oxidative deamination. O-Methylation is catalyzed by the enzyme catechol-O-methyltransferase (COMT). Oxidative deamination is promoted by monoamine oxidase (MAO). MAO is important in regulating the catecholamine stores within the peripheral sympathic nerve endings. For a more complete description of the biosynthesis and metabolism of the catecholamines, see Harrison, supra, pages 409-412.
The pyridoxines are a group of B6 vitamins which include pyridoxine, pyridoxal, and pyridoxamine and their five-phosphate esters. The coenzyme formed in vivo is pyridoxal-5-phosphate. The compounds owe their enzymatic activity to conversion in vivo to pyridoxal-5-phosphate. Pyridoxal-5-phosphate acts as a cofactor for a large number of enzymes involved in amino acid metabolism, including transaminases, synthetases, and hydroxylases, and is a known enzyme cofactor in the biosynthesis of norepinephrine from phenylalanine and tyrosine. Ascorbic acid plays a role as an enzymatic cofactor in hydroxylation reactions. Accordingly, ascorbic acid participates in the biosynthesis of DOPA from tyrosine and in the biosynthesis of norepinephrine from dopamine. Goodman and Gilman's, The Pharmacological Basis of Therapeutics, 7th Edition, edited by Gilman, A. G. et al, Macmillan Publishing Company, New York, N.Y. (1985) pp. 82, 1559-1560.
Contrary to the idea that brain catecholamine levels cannot be effectively raised by tyrosine administration, it has been observed that increasing brain tyrosine levels does increase brain DOPA levels. Conversely, decreases in brain DOPA levels could be produced in rats by decreasing brain tyrosine levels. Wurtman et al., Science 185:183-184 (1974). Increased brain levels of tyrosine were achieved by administering tyrosine itself.
U.S. Pat. No. 4,470,987 to Wurtman et al., discloses a composition for reducing the risk of ventricular fibrilation in animals by administering tyrosine or a tyrosine precursor, either alone or in combination with a further substance known to reduce the risk of ventricular fibrillation. According to the disclosure, increased synaptic norepinephrine levels are obtained by administering tyrosine. Wurtman also discloses that phenylalanine can, in low doses, be used in place of tyrosine Phenylalanine and tyrosine act by increasing the release of catecholamines (dopamine, norepinephine, or epinephrine) into synapses which in turn reduce the firing frequency of the sympathetic neurons running to the heart, thereby decreasing cardiac excitability and vulnerability.
U.S. Pat. No. 4,598,094, to Wurtman, discloses the concomitant administration of tyrosine with an indirect-acting sympathomimetic drug to increase the level of norepinephrine released in the sympathetic neuron synapses. The claimed invention is a composition and a process for preventing tachyphylaxis, caused by amphetamine administration, comprising concomitantly administering amphetamine with a catecholamine precursor such as L-tyrosine. L-tyrosine serves to replete norepinephrine which had been depleted by the indirect acting sympathomimetic drugs.
Desipramine is a member of the tricyclic family of antidepressants, which block the presynaptic re-uptake of norepinephrine in the central nervous system. Other tricyclic antidepressants include imipramine hydrochloride, imipramine pamoate, amitriptyline hydrochloride, and protriptyline hydrochloride. These compounds have anti-anxiety and sedative properties which make them useful in the treatment of mild depression. See Remington's Pharmaceutical Sciences, edited by R. Osol, Mack Publishing Company, Easton, Pa., page 1038 (1980).
Desipramine has been reported to be effective in decreasing depressive symptoms of phencyclidine and cocaine abusers. Phencyclidine and cocaine have been shown to release dopamine and norepinephrine presynaptically and are equipotent to amphetamine in blocking catecholamine reuptake. Giannini, A. J., et al., J. Clin. Pharmacol. 26:211-214 (1986). The authors hypothesize that the tricyclic antidepressants are effective in treating cocaine abuse due to the induction of receptor subsensitivity. The suggestion that desipramine is effective in PCP withdrawal because of its ability to block reuptake of norepinephrine was not supported by their findings. Re-uptake blockade is felt to occur rather quickly, whereas alteration of receptors occurs after three to four weeks. The authors report that a two-week time period after starting desipramine was necessary in order to obtain the therapeutic effect in both cocaine and PCP abusers.
Desipramine has also been reported to enhance the anorectic effects of d-amphetamine, phentermine, and diethylpropion, but did not modify those of phenmetrazine and chlorphentermine. Menon, M. K., et al., Eur. J. Pharmacol. 12:156-160 (1970). The authors hypothesize that potentiation and prolongation of the effects of d-amphetamine, phentermine, and diethylpropion by desipramine are probably due to interference with their metabolism, leading to an increase in the half-life of the substances in the body.
The clinical effect of desipramine and imipramine in depressed patients has been found to be related to the plasma ratios of tryptophan and tyrosine to competing amino acids. Miller, S. E., et al., Neuropsychobiology 13:160-166 (1985). The authors concluded that determination of pretreatment plasma ratios of tryptophan and tyrosine to competing amino acids may serve as a useful and convenient direction for the adjustment of serum imipramine and desipramine to optimal therapeutic levels in individual depressives.
Thus, a medicament comprising the combination of a norepinephrine precursor and a norepinephrine re-uptake inhibitor, said medicament useful for the treatment of obesity, depression, drug abuse, or narcolepsy is not taught or suggested by the prior art.